The Controversial p.Arg127His Mutation in GJB2: Report on Three Portuguese Hearing Loss Family Cases

Abstract

Mutations in the GJB2 gene account for up to 50% of hereditary nonsyndromic hearing loss in several populations. Over 200 mutations are already described in this gene, and three of them, c.35delG, c.167delT, and c.235delC, are the most frequent in Caucasians, Ashkenazi Jews, and Asians, respectively. Most of GJB2 hearing loss-related mutations are recessive, but a few dominant alleles have also been described. Apart from the clearly pathogenic mutations, there are some other variants whose pathogenicity is still controversial, such as p.Met34Thr, p.Val37Ile, p.Arg127His, and p.Val153Ile. The p.Arg127His allele has been found in some mono- and biallelic hearing-impaired patients from several countries. In this article we report on some Portuguese patients harboring this mutation. Taking into consideration the analysis of these Portuguese cases as well as the genetic and functional data regarding p.Arg127His available in the literature, we conclude that this variant may be a cause of hearing loss depending on environmental factors and/or genetic background.

Genetic Spectrum of Autosomal Recessive Non-Syndromic Hearing Loss in Pakistani Families

“…Based upon the higher carrier frequency in patients as well as controls, Padma et al [30] suggested that it is unlikely that this variant plays a pathogenic role in deafness. However, Matos et al [32] have proposed that this mutation is likely to be pathogenic when influenced by other unknown genetic or environmental factors [32]. In the EVS, however, no homozygous occurrence of the mutated allele has been reported to date (Table S1).…”

DFNB1-associated deafness in Portuguese cochlear implant users: Prevalence and impact on oral outcome

“…After isolation of genomic DNA from FTA cards using standard procedures, screening for GJB2 mutations was performed by DNAbased sequencing of the GJB2 coding region, as described previously [15]. A multiplex PCR was used for detection of the GJB6 deletions, del(GJB6-D13S1830) and del(GJB6-D13S1854) [6].…”

The controversial p.Met34Thr variant in GJB2 gene: Two siblings, one genotype, two phenotypes

“…Molecular analysis of GJB2 gene (Cx26) was performed, including searching for mutations in the coding region and receptor splicing site by automated sequencing. PCR amplification of GJB2 coding exon and receptor splice site was made according to Matos et al (2010) [8]. After bidirectional sequencing, the electrophoretograms were evaluated by visual inspection and pairwise alignment to reference sequences using NCBI's BLAST (Basic Local Alignment Search Tool).…”